(MDS) and acute myeloid leukemia (AML) have been made through unbiased gene discovery approaches. Similar advances have been made in understanding the genetic basis of rare cases of familial MDS and AML. Currently, germline mutations in genes encoding transcription factors, including RUNX1, CEBPA, and more recently GATA2, 1-8 have been identified in patients with familial MDS/AML. In patients with familial MDS/AML, however, there is great heterogeneity in the age of disease onset as well as the clinical characteristics of the myeloid malignancy which develops in affected members of such families. For instance, in the largest single survey of disease phenotypes in individuals with germline GATA2 mutations, 50% of patients were without symptoms at the age of 20 and 16% continued to remain without symptoms by the age of 40. 7 In this issue of Haematologica, West et al. begin to unravel the genetic alterations that frequently occur together and collaborate with germline GATA2 mutations to promote the development of MDS and AML. 8 In 2011, four papers were published identifying heterozygous germline GATA2 mutations as the cause of four previously described clinical syndromes: primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome), 1 RUNX1/CEBPA wild-type familial AML/MDS, 2 monocytopenia and mycobacterial infections (MonoMAC syndrome), 9 and the dendritic cell, monocyte, B and NK lymphoid deficiency syndrome (DCML deficiency). 10 Since then, approximately 200 patients with germline GATA2 mutations have been described (Table 1), each presenting with a variety of clinical presentations but all with a high risk of developing MDS/AML. In a summary of these studies, approximately 70% of GATA2-deficient individuals appear to develop MDS or AML in their lifetime.

Interestingly, attempts have been made to correlate the risk and outcomes of myeloid malignancy in patients with germline GATA2 mutations with the genotype of the GATA2 mutation present, but this has been limited by the number of patients. 7 Although monosomy 7 clearly appears to be enriched in GATA2-deficient individuals who develop MDS and AML (30% of individuals; Table 1), the first clue to a specific molecular abnormality which might be an important collaborating genetic event for the development of overt myeloid malignancy in GATA2 mutant families came from recent work by Bodor et al. 3 In this prior study of a germline GATA2-mutant kindred, somatic ASXL1 mutations were present exclusively in the two members of the family who developed MDS/AML. This finding strongly suggested that ASXL1 mutations might be an important trigger for the development of overt disease in GATA2-mutated patients.